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- PDB-7q7t: Crystal structure of human BCL6 BTB domain in complex with compound 7 -

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Basic information

Entry
Database: PDB / ID: 7q7t
TitleCrystal structure of human BCL6 BTB domain in complex with compound 7
Components
  • ALA-TRP-VAL-ILE-PRO-ALA
  • B-cell lymphoma 6 protein
KeywordsTRANSCRIPTION / Inhibitor
Function / homology
Function and homology information


regulation of memory T cell differentiation / negative regulation of mitotic cell cycle DNA replication / intronic transcription regulatory region sequence-specific DNA binding / negative regulation of isotype switching to IgE isotypes / negative regulation of plasma cell differentiation / negative regulation of T-helper 2 cell differentiation / isotype switching to IgE isotypes / negative regulation of mast cell cytokine production / regulation of germinal center formation / negative regulation of mononuclear cell proliferation ...regulation of memory T cell differentiation / negative regulation of mitotic cell cycle DNA replication / intronic transcription regulatory region sequence-specific DNA binding / negative regulation of isotype switching to IgE isotypes / negative regulation of plasma cell differentiation / negative regulation of T-helper 2 cell differentiation / isotype switching to IgE isotypes / negative regulation of mast cell cytokine production / regulation of germinal center formation / negative regulation of mononuclear cell proliferation / plasma cell differentiation / paraspeckles / germinal center formation / pyramidal neuron differentiation / regulation of immune system process / type 2 immune response / positive regulation of regulatory T cell differentiation / T-helper 2 cell differentiation / negative regulation of B cell apoptotic process / positive regulation of cell motility / negative regulation of Rho protein signal transduction / FOXO-mediated transcription of cell death genes / negative regulation of cell-matrix adhesion / regulation of T cell proliferation / negative regulation of Notch signaling pathway / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / B cell proliferation / regulation of cell differentiation / negative regulation of cellular senescence / Rho protein signal transduction / regulation of immune response / erythrocyte development / heterochromatin formation / positive regulation of B cell proliferation / regulation of cytokine production / positive regulation of neuron differentiation / cell-matrix adhesion / transcription corepressor binding / cell motility / cell morphogenesis / protein localization / negative regulation of cell growth / chromatin DNA binding / DNA-binding transcription repressor activity, RNA polymerase II-specific / sequence-specific double-stranded DNA binding / regulation of cell population proliferation / regulation of inflammatory response / actin cytoskeleton organization / spermatogenesis / Interleukin-4 and Interleukin-13 signaling / DNA-binding transcription factor binding / sequence-specific DNA binding / transcription by RNA polymerase II / inflammatory response / positive regulation of apoptotic process / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of DNA-templated transcription / DNA damage response / chromatin binding / nucleolus / Golgi apparatus / negative regulation of transcription by RNA polymerase II / nucleoplasm / identical protein binding / nucleus / metal ion binding
Similarity search - Function
BTB/POZ domain / BTB domain profile. / Zinc finger, C2H2 type / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / zinc finger / Zinc finger C2H2 type domain profile. / Zinc finger C2H2 superfamily / SKP1/BTB/POZ domain superfamily / Zinc finger C2H2 type domain signature. / Zinc finger C2H2-type
Similarity search - Domain/homology
Chem-9FW / B-cell lymphoma 6 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.46 Å
AuthorsRodrigues, M.J. / Le Bihan, Y.-V. / van Montfort, R.L.M.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Cancer Research UKC309/A11566 United Kingdom
CitationJournal: J.Med.Chem. / Year: 2022
Title: Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors.
Authors: Davis, O.A. / Cheung, K.J. / Brennan, A. / Lloyd, M.G. / Rodrigues, M.J. / Pierrat, O.A. / Collie, G.W. / Le Bihan, Y.V. / Huckvale, R. / Harnden, A.C. / Varela, A. / Bright, M.D. / Eve, P. ...Authors: Davis, O.A. / Cheung, K.J. / Brennan, A. / Lloyd, M.G. / Rodrigues, M.J. / Pierrat, O.A. / Collie, G.W. / Le Bihan, Y.V. / Huckvale, R. / Harnden, A.C. / Varela, A. / Bright, M.D. / Eve, P. / Hayes, A. / Henley, A.T. / Carter, M.D. / McAndrew, P.C. / Talbot, R. / Burke, R. / van Montfort, R.L.M. / Raynaud, F.I. / Rossanese, O.W. / Meniconi, M. / Bellenie, B.R. / Hoelder, S.
History
DepositionNov 9, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 15, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 6, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: B-cell lymphoma 6 protein
B: ALA-TRP-VAL-ILE-PRO-ALA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,02610
Polymers15,1932
Non-polymers8348
Water3,441191
1
A: B-cell lymphoma 6 protein
B: ALA-TRP-VAL-ILE-PRO-ALA
hetero molecules

A: B-cell lymphoma 6 protein
B: ALA-TRP-VAL-ILE-PRO-ALA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,05320
Polymers30,3854
Non-polymers1,66816
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_545x,x-y-1,-z+1/61
Buried area7370 Å2
ΔGint-48 kcal/mol
Surface area13940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.568, 68.568, 167.254
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-338-

HOH

21A-374-

HOH

31A-434-

HOH

41A-466-

HOH

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AB

#1: Protein B-cell lymphoma 6 protein / BCL-6 / B-cell lymphoma 5 protein / BCL-5 / Protein LAZ-3 / Zinc finger and BTB domain-containing ...BCL-6 / B-cell lymphoma 5 protein / BCL-5 / Protein LAZ-3 / Zinc finger and BTB domain-containing protein 27 / Zinc finger protein 51


Mass: 14536.915 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCL6, BCL5, LAZ3, ZBTB27, ZNF51 / Plasmid: pET48b / Production host: Escherichia coli BL21 (bacteria) / Variant (production host): AI / References: UniProt: P41182
#2: Protein/peptide ALA-TRP-VAL-ILE-PRO-ALA


Mass: 655.784 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 5 types, 199 molecules

#3: Chemical ChemComp-9FW / 2-chloranyl-4-[[(2S)-2,7-dimethyl-5,6-bis(oxidanylidene)-2,3-dihydro-1H-[1,4]oxazepino[6,5-c]quinolin-10-yl]amino]pyridine-3-carbonitrile


Mass: 409.826 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H16ClN5O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 191 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 2 microliter of the BCL6-BTB/WVIP complex at 4 mg/mL plus 1 microliter of a crystallisation solution consisting of 1 M K2HPO4, 0.7 M NaH2PO4, 75 mM sodium acetate buffer pH 4.5 and 2 % DMSO, ...Details: 2 microliter of the BCL6-BTB/WVIP complex at 4 mg/mL plus 1 microliter of a crystallisation solution consisting of 1 M K2HPO4, 0.7 M NaH2PO4, 75 mM sodium acetate buffer pH 4.5 and 2 % DMSO, against 350 microliter of crystallisation solution.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9282 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Apr 29, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9282 Å / Relative weight: 1
ReflectionResolution: 1.46→48.42 Å / Num. obs: 41379 / % possible obs: 100 % / Redundancy: 12.4 % / Biso Wilson estimate: 24.98 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.061 / Rpim(I) all: 0.018 / Rrim(I) all: 0.063 / Net I/σ(I): 17.1 / Num. measured all: 512195 / Scaling rejects: 78
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.46-1.4812.82.3422575220050.5410.6762.4391.199.9
8-48.4210.40.018355234210.0060.01988.799.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
BUSTER2.10.4 (24-FEB-2021)refinement
Aimless0.5.14data scaling
PHASERphasing
PDB_EXTRACT3.24data extraction
DIALSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3BIM

3bim


Resolution: 1.46→48.42 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.954 / SU R Cruickshank DPI: 0.055 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.062 / SU Rfree Blow DPI: 0.061 / SU Rfree Cruickshank DPI: 0.056
RfactorNum. reflection% reflectionSelection details
Rfree0.2126 1985 4.81 %RANDOM
Rwork0.1953 ---
obs0.1962 41286 100 %-
Displacement parametersBiso max: 101.89 Å2 / Biso mean: 32.56 Å2 / Biso min: 17.95 Å2
Baniso -1Baniso -2Baniso -3
1--1.9051 Å20 Å20 Å2
2---1.9051 Å20 Å2
3---3.8102 Å2
Refine analyzeLuzzati coordinate error obs: 0.2 Å
Refinement stepCycle: final / Resolution: 1.46→48.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1018 0 54 199 1271
Biso mean--41.09 52.9 -
Num. residues----131
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d425SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes231HARMONIC5
X-RAY DIFFRACTIONt_it1197HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion158SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies17HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1000SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1197HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg1633HARMONIC20.84
X-RAY DIFFRACTIONt_omega_torsion3.17
X-RAY DIFFRACTIONt_other_torsion13.23
LS refinement shellResolution: 1.46→1.47 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.3155 37 4.48 %
Rwork0.31 789 -
all0.3102 826 -
obs--99.88 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.95280.81771.20520.67631.73372.48620.03930.066-0.04030.1695-0.019-0.0530.2234-0.075-0.0203-0.007-0.0305-0.01680.0144-0.01580.003132.1953-26.802313.5915
20.9916-1.1899-1.13511.85290.62632.71660.0321-0.06270.11170.31910.1734-0.31530.04250.3103-0.20550.0591-0.0284-0.0382-0-0.04740.025640.0825-13.506130.5353
30.18130.5161-0.27621.74730.84811.1920.13990.0420.00960.0785-0.046-0.0381-0.0718-0.0916-0.0940.0312-0.03820.0291-0.0301-0.01520.014333.5167-10.537524.7752
41.08210.779-1.81510.6702-0.41975.06650.1354-0.0432-0.09960.2059-0.23620.08220.23040.160.10090.0745-0.14020.06460.0163-0.0294-0.045222.3126-23.106333.1415
50.94671.3206-1.61551.6237-1.00841.87080.25110.02840.19730.2129-0.29030.1418-0.0872-0.27050.03930.0285-0.06350.06980.0145-0.060.018323.5496-10.653631.0697
64.08080.9548-3.52024.95750.27630-0.16320.5140.16920.1984-0.01780.39870.1536-0.16030.181-0.0786-0.10210.11020.1029-0.11190.008113.8445-15.188531.2021
75.03791.2039-0.6977-0.27911.21790.73690.0889-0.0283-0.1022-0.0620.02580.02190.10360.0651-0.1147-0.0599-0.0478-0.02010.0927-0.07670.004419.354-32.86872.1342
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|5 - 33}A5 - 33
2X-RAY DIFFRACTION2{A|34 - 46}A34 - 46
3X-RAY DIFFRACTION3{A|47 - 92}A47 - 92
4X-RAY DIFFRACTION4{A|93 - 101}A93 - 101
5X-RAY DIFFRACTION5{A|102 - 114}A102 - 114
6X-RAY DIFFRACTION6{A|115 - 129}A115 - 129
7X-RAY DIFFRACTION7{B|0 - 5}B0 - 5

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